TDO2

protein-coding

tryptophan 2,3-dioxygenase

Gene summary

This gene encodes a heme enzyme that plays a critical role in tryptophan metabolism by catalyzing the first and rate-limiting step of the kynurenine pathway. Increased activity of the encoded protein and subsequent kynurenine production may also play a role in cancer through the suppression of antitumor immune responses, and single nucleotide polymorphisms in this gene may be associated with autism. [provided by RefSeq, Feb 2012]

MANE transcript

NM_005651.4

Inheritance

AR, AD

ClinVar variants

U:53B:5

Top phenotype

Hypertryptophanemia

gnomAD constraint

pLI —, LoF o/e 0.71

Max pathogenic AF

—

Genomic locus

chr4:155,854,738-155,920,406

External References & Databases

Ensembl (ENSG00000151790)

Transcript & Mutation Effects

hg38 • Region Span ~65.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

familial hypertryptophanemiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010907

Submitter: Orphanet

familial hypertryptophanemiaLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0010907

Submitter: PanelApp Australia

familial hypertryptophanemiaLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0010907

Submitter: Labcorp Genetics (formerly Invitae)

familial hypertryptophanemiaLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0010907

Submitter: ClinGen

*TDO2* was first reported in relation to autosomal recessive hypertryptophanemia in 2017 (Ferreira P, et al., 2017, PMID: 28285122). It results in the biochemical phenotype of persistent hypertryptophanemia and hyperserotoninemia, but without any discernable clinical phenotype. Unbiased ascertainment by newborn screening strongly suggests that this is a benign biochemical variant of no clinical significance (PMIDs: 28285122). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Two unique variants (missense and frameshift) have been reported in the single human case (PMID: 28285122). This gene-disease association is supported by its biochemical function in tryptophan metabolism (PMID: 18027945) and a knockout mouse model (PMID: 19323847). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This gene-disease pair was previously evaluated by the Aminoacidopathy GCEP on 07/10/2020. It was reevaluated on 10/24/2023. As a result of this reevaluation, the classification remained Limited with no new evidence identified.

Clinical Genomic Database (CGD)

HypertryptophanemiaAD

Manifestation: Biochemical

Intervention: General

Rationale: The clinical relevance of the condition is unclear

Refs: 28285122

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TDO2 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 49

TDO2-related disorderTotal: 3

not providedTotal: 2

Familial hypertryptophanemiaTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005651.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				2 clinvar	1 clinvar	3
missense			51 clinvar	1 clinvar	1 clinvar	53
nonsense						0
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	0	0	53	3	2	58

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 53 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005651.4	RefSeq	NP_005642.1	12	MANE Select
ENST00000536354.3	Ensembl	ENSP00000444788.2	12	MANE Select
ENST00000506072.5	Ensembl	ENSP00000423394.1	2	Standard
ENST00000507590.5	Ensembl	ENSP00000424384.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Tryptophan metabolism - Homo sapiens (human)
Tryptophan Metabolism
NAD Biosynthesis II (from tryptophan)
NAD+ biosynthetic pathways
Amino Acid metabolism

Biological Process

tryptophan catabolic process
tryptophan catabolic process to kynurenine
tryptophan catabolic process to acetyl-CoA
protein homotetramerization
oxidation-reduction process

Molecular Function

tryptophan 2,3-dioxygenase activity
protein binding
amino acid binding
oxygen binding
heme binding

Cellular Component

cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000536354
Coding exons: 12
Length: 65669
Individuals with no LoFs: 125653
Homozygous LoFs: 1
Heterozygous LoFs: 94
Defined: 125748
p: 0.000378

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.221	210	201	1.04	0.00000987	2651
Missense (PolyPhen)		91	72.899	1.2483		952
Synonymous	-0.303	77	73.7	1.04	0.00000357	718
Loss of Function	1.40	19	26.8	0.708	0.00000156	316

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00018	0.00018	rare
Latino/Admixed American	0.00050	0.00049	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00033	0.00033	rare
Finnish	0.00019	0.00018	rare
European (Non-Finnish)	0.00048	0.00047	rare
South Asian	0.00031	0.00026	rare
Other	0.00065	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Heme-dependent dioxygenase that catalyzes the oxidative cleavage of the L-tryptophan (L-Trp) pyrrole ring and converts L- tryptophan to N-formyl-L-kynurenine. Catalyzes the oxidative cleavage of the indole moiety. {ECO:0000255|HAMAP-Rule:MF_03020, ECO:0000269|PubMed:25066423, ECO:0000269|PubMed:27762317, ECO:0000269|PubMed:28285122}.;
Disease: DISEASE: Hypertryptophanemia (HYPTRP) [MIM:600627]: An autosomal recessive condition characterized by persistent hypertryptophanemia and hyperserotoninemia. {ECO:0000269|PubMed:28285122}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.359

Intolerance Scores

LoFtool: 0.387
RVIS EVS: 0
RVIS percentile EVS: 53.73

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.754

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium